Many drugs are not suitable for passive drug delivery because of their size, ionic charge characteristics and hydrophilicity. One method of overcoming this limitation in order to achieve transdermal administration of such drugs is the use of electrical current or an electrical potential gradient to actively transport drugs into the body, as for example, through intact skin or other tissues. This concept is based upon basic principles of electrochemistry and is defined as electrically-assisted transport, hereinafter referred to as "electrotransport". An electrochemical cell in its simplest form consists of two electrodes and associated half cell reactions, between which electrical current can flow. Electrical current flowing through the metal portion of the circuit is carried by electrons (electronic conduction), while current flowing through the liquid phase is carried by ions (ionic conduction). Current flows as an electrical charge is transferred to chemical species in solution by means of oxidation and reduction charge transfer reactions at the electrode surfaces. A detailed description of the electrochemical processes involved in electrically-assisted drug transport can be found in electrochemistry texts such as J. S. Newman, Electrochemical Systems (Prentice Hall, 1973) and A. J. Bard & L. R. Faulkner, Electrochemical Methods, Fundamentals and Applications (John Wiley & Sons, 1980). Therefore, only pertinent portions will be presented here.
As electrical current flows, oxidation and reduction of some chemical species take place. A variety of electrochemical reactions can be utilized, and these fall into two classes. In one class, the electrode material participates in the charge transfer reaction; i.e., the electrode material is consumed or generated. In the other class, the electrode material behaves as a catalyst; i.e., the reduced and oxidized species exist in solution and the charge transfer reaction is catalyzed at the electrode surface. An example of the former is represented by : EQU Zn.revreaction.Zn.sup.+2 +2e.sup.-
or EQU Ag+Cl.sup.- .revreaction.AgCl+e.sup.-
where the forward reaction is the oxidation or anodic process and the reverse reaction is the reduction or cathodic process.
Examples of electrochemical reactions involving species independent of the electrode materials are the hydroquinone/quinone and the ferrous/ferric ion couples: EQU H.sub.2 Q.revreaction.Q+2H.sup.+ +2e.sup.-
and EQU Fe.sup.++ Fe.sup.+++ 30 e.sup.-
Again, the forward reaction is the anodic process and the reverse reaction is cathodic. These reactions are catalyzed by an appropriate polarized surface.
When electrical charge is either generated or consumed at an electrode surface, ionic species must be transported to maintain electroneutrality throughout the system. Electrically-assisted transport or electrotransport, is defined as the mass transport of a particular chemical species through a biological interface or membrane when an electrical potential gradient is imposed across said interface or membrane Three physical processes contribute to this transport: passive diffusion, electromigration and convection.
In applying these principles to drug delivery, the drug being delivered can be electrically-assisted into the skin. There are a number of categories in which drug delivery systems utilizing electrotransport principles can offer major therapeutic advantages. See P. Tyle & B. Kari, "Iontophoretic Devices", in DRUG DELIVERY DEVICES, pp.421-454 (1988).
Even though the concept of electrotransport in drug delivery is there is a continuing need to develop systems which overcome the problems associated with known electrotransport devices. Typical electrotransport systems combine the agent or drug to be delivered with other electrolyte components such as buffers, salts and electrochemical reactants. In such a system, these species could either react directly with the drug or change the composition of the drug reservoir such that the performance of the delivery system is adversely affected. For example, a reaction product capable of causing precipitation of the drug which subsequently blocks and insulates the electrode surface would be a detriment to the overall system and process. Changes in electrolyte pH can yield drastic changes in transport characteristics and, at some pH values, damage to the skin could occur. Damage to the skin can also occur due to contact with metal ions produced during discharge of the electrodes. In addition, control of the ionic strength of the donor electrolyte can also be very important. This invention addresses the problem by separating the electrolyte from the drug by means of a selectively permeable membrane.